2brh: Difference between revisions
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==Overview== | ==Overview== | ||
We report the discovery, synthesis, and crystallographic binding mode of, novel furanopyrimidine and pyrrolopyrimidine inhibitors of the Chk1, kinase, an oncology target. These inhibitors are synthetically tractable, and inhibit Chk1 by competing for its ATP site. A chronological account, allows an objective comparison of modeled compound docking modes to the, subsequently obtained crystal structures. The comparison provides insights, regarding the interpretation of modeling results, in relationship to the, multiple reasonable docking modes which may be obtained in a kinase-ATP, site. The crystal structures were used to guide medicinal chemistry, efforts. This led to a thorough characterization of a pair of, ligand-protein complexes which differ by a single hydrogen bond. An, analysis . | We report the discovery, synthesis, and crystallographic binding mode of, novel furanopyrimidine and pyrrolopyrimidine inhibitors of the Chk1, kinase, an oncology target. These inhibitors are synthetically tractable, and inhibit Chk1 by competing for its ATP site. A chronological account, allows an objective comparison of modeled compound docking modes to the, subsequently obtained crystal structures. The comparison provides insights, regarding the interpretation of modeling results, in relationship to the, multiple reasonable docking modes which may be obtained in a kinase-ATP, site. The crystal structures were used to guide medicinal chemistry, efforts. This led to a thorough characterization of a pair of, ligand-protein complexes which differ by a single hydrogen bond. An, analysis indicates that this hydrogen bond is expected to contribute a, fraction of the 10-fold change in binding affinity, adding a valuable, observation to the debate about the energetic role of hydrogen bonding in, molecular recognition. | ||
==About this Structure== | ==About this Structure== | ||
2BRH is a | 2BRH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with DFW as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2BRH OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
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Revision as of 16:22, 5 November 2007
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STRUCTURE-BASED DESIGN OF NOVEL CHK1 INHIBITORS: INSIGHTS INTO HYDROGEN BONDING AND PROTEIN-LIGAND AFFINITY
OverviewOverview
We report the discovery, synthesis, and crystallographic binding mode of, novel furanopyrimidine and pyrrolopyrimidine inhibitors of the Chk1, kinase, an oncology target. These inhibitors are synthetically tractable, and inhibit Chk1 by competing for its ATP site. A chronological account, allows an objective comparison of modeled compound docking modes to the, subsequently obtained crystal structures. The comparison provides insights, regarding the interpretation of modeling results, in relationship to the, multiple reasonable docking modes which may be obtained in a kinase-ATP, site. The crystal structures were used to guide medicinal chemistry, efforts. This led to a thorough characterization of a pair of, ligand-protein complexes which differ by a single hydrogen bond. An, analysis indicates that this hydrogen bond is expected to contribute a, fraction of the 10-fold change in binding affinity, adding a valuable, observation to the debate about the energetic role of hydrogen bonding in, molecular recognition.
About this StructureAbout this Structure
2BRH is a Single protein structure of sequence from Homo sapiens with DFW as ligand. Active as Transferred entry: 2.7.11.1, with EC number 2.7.1.37 Structure known Active Site: AC1. Full crystallographic information is available from OCA.
ReferenceReference
Structure-based design of novel Chk1 inhibitors: insights into hydrogen bonding and protein-ligand affinity., Foloppe N, Fisher LM, Howes R, Kierstan P, Potter A, Robertson AG, Surgenor AE, J Med Chem. 2005 Jun 30;48(13):4332-45. PMID:15974586
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OCA- Pages with broken file links
- Homo sapiens
- Single protein
- Transferred entry: 2.7.11.1
- Fisher, L.M.
- Foloppe, N.
- Howes, R.
- Kierstan, P.
- Potter, A.
- Robertson, A.G.S.
- Surgenor, A.E.
- DFW
- Atp-binding
- Cell cycle
- Dna damage
- Drug design
- Furanopyrimidine
- Kinase
- Molecular recognition
- Nuclear protein
- Oncology
- Phosphorylation
- Polymorphism
- Pyrrolopyrimidine
- Serine/threonine-protein kinase
- Transferase